1. Field of the Invention
The present invention concerns processes to produce prostaglandins.
2. Background Information
There are few substances that currently command more widespread interest in biological circles than do the prostaglandins and the related products of arachidonic acid metabolism. Although their history extends back to the early 1930s, it was the isolation, characterization, and synthesis of the representative compounds in the early 1960s that generated such intense interest. The reasons are not hard to find. The prostaglandins are among the most prevalent of autacoids and have been detected in almost every tissue and body fluid; their production increases in response to astonishingly diverse stimuli; they produce, in minute amounts, a remarkably broad spectrum of effects that embraces practically every biological function; and inhibition of their biosynthesis is now recognized as a mechanism of some of the most widely used therapeutic agents, the nonsteroidal anti-inflammatory drugs such as aspirin.
A harbinger of this remarkable development was the observation made in 1930 by two American gynecologists, Kurzrok and Lieb, that strips of human uterus relax or contract when exposed to human semen. A few years later, Goldblatt in England and Euler in Sweden independently reported smooth-muscle-contracting and vasodepressor activity in seminal fluid and accessory reproductive glands, and Euler identified the active material as a lipid-soluble acid, which he named "prostaglandin". More than 20 years were to pass before technical advances allowed the demonstration that prostaglandin was in fact a family of compounds of unique structure, permitted the isolation in crystalline form of two prostaglandins, prostaglandin E.sub.1 (PGE.sub.1) and PGF.sub.1.alpha., and led to the elucidation of their structures in 1962. Soon, more prostaglandins were characterized and, like the others, proved to be 20-carbon unsaturated carboxylic acids with a cyclopentane ring.
When the general structure of the prostaglandins became apparent, their kinship with essential fatty acids was recognized, and in 1964 Bergstrom and coworkers and van Dorp and associates independently achieved the biosynthesis of PGE.sub.2 from arachidonic acid using homogenates of sheep seminal vesicle.
Until recently it was believed that PGE.sub.2 and PGF.sub.2.alpha. were the most important prostaglandins. Indeed, thousands of analogs of these compounds were made in the largely frustrated hope that compounds of therapeutic value with a greater selectivity of action would emerge. However, since 1973, several discoveries have caused a radical shift in emphasis away from PGEs and PGFs. The first was the isolation and identification of two unstable cyclic endoperoxides, prostaglandin G.sub.2 (PGG.sub.2 or 15-OOH PGH.sub.2) and prostaglandin H.sub.2 (PGH.sub.2). Later came the elucidation of the structure of thromboxane A.sub.2 (TXA.sub.2) and that of its degradation product, thromboxane B.sub.2 (TXB.sub.2) and then the discovery of prostacyclin (PGI.sub.2). These findings, coupled with the elucidation of a different enzymatic pathway (a lipoxygenase), which converts arachidonic acid to compounds such as 12-hydroperoxyeicosatertraenoic acid (HPETE) and 12-hydroxyeicosatetraenoic acid (HETE), have led to the realization that the "classically known" prostaglandins constitute only a fraction of the physiologically active products of arachidonic acid metabolism.
The notion of synthesizing prostaglandins by dialkylation of an .alpha.,.beta.-unsaturated ketone goes back to the early days of the field. For comprehensive reviews of prostanoid syntheses, see: (a) Bindra, J. S.; Bindra, R., Prostaglandin Synthesis; Academic Press: New York, 1977; (b) Mitra, A., Synthesis of Prostaglandins; Wiley-Interscience: New York, 1977; (c) Garcia, G. A.; Maldonado, L. A.; Crabbe, P., Prostaglandin Research; Crabbe, P., Ed.; Academic Press: New York, 1977; Chapter 6; (d) New Synthetic Routes to Prostaglandins and Thromboxanes; Roberts, S. M., Scheinmann, F., Eds.; Academic Press: London, 1982.
The first success in a fully functionalized setting was realized by Stork, G. and Isobe, M., J. Am. Chem. Soc., 1975, 97, 4745. Major advances in conciseness and efficiency have been introduced by Noyori et al (Suzuki, M., Kawagishi, T.; Suzuki, I.; Noyori, R., Tetrahedron Lett.; 1982, 23, 4057 and Suzuki, M.; Yanagisawa, A.; Noyori, R., J. Am. Chem. Soc., 1988, 110, 4718); Johnson et al (Johnson, C. R.; Penning, T. D., J. Am. Chem. Soc., 1988, 110, 4726) and Corey et al (Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada, Y., Tetrahedron Lett., 1986, 27, 2199).
While there have been countless variations, a common theme is apparent. Addition of a nucleophilic version of the C.sub.13 -C.sub.20 ("lower-chain") to C.sub.12 generates a C.sub.8 -C.sub.9 enolate which is trapped with an electrophile suitable for construction of the C.sub.7 -C.sub.1 ("upper") chain. In these schemes, the R enatiomer is employed. The stereochemical rationale of this method is that the organometallic nucleophile (Nu) attacks anti to the OP group and the electrophile attacks C.sub.8 anti to the "lower" chain installed at C.sub.12. The proper configuration at C.sub.15 is achieved either from the use of a suitable educt or by reduction of the C.sub.15 ketone (Noyori, R.; Tomino, I.; Nishizawa, M., J. Am. Chem. Soc., 1979, 101, 5843; Corey, E. J.; Becker, K. B.; Varma, R. K., J. Am. Chem. Soc., 1972, 94, 8616).
The general outlines of the previous three-component strategy are implied in the following Scheme I, where PGF.sub.2.alpha. is the goal system. ##STR3##
There has also been interest in preparing prostaglandins that were heretofore produced by enzymatic conversion of arachidonic acid (Hoffmann, V., Meese, C. O., Hecker, M. and Volker, V., Tetrahedron Lett., 1987, 28, 5655-5658; Hecker, M., Ullrich, V., Fischer, C. and Meese, C. O., Eur. J. Biochem., 1987, 109 113-123).
The principal 9.alpha.,11.alpha.-endoperoxides arising from the in vivo oxidation of arachidonate in the presence of PGH synthase, contain a trans 13,14-double bond and either 15 S-hydroperoxy (PGG.sub.2) or 15S hydroxy (PGH.sub.2) functions (Samuelson, B., Angew Chem. Int. Ed. Engl., 22, 805, 1983 and Hecker, M., Hatzelmann, A., Ullrich, V., Biochem. Pharmacol., 36, 851 (1987)). Surprisingly, it was recently shown that this process also produces allylic ( .sup.14) isomers of the above, bearing oxygen substitution at C.sub.13. Reduction of this endoperoxide gives rise to an allylic isomer of PGF.sub.2.alpha. (Hecker, M., Hatzelmann, A., Ullrich, V., Biochem. Pharmacol., 36, 851 (1987); Hecker, M., Ullrich, V., Fischer, C. and Meese, O. C., Eur. J. Biochem., 113, 1987). That this prostaglandin is properly represented by structure 1' was demonstrated by Hoffman et al, supra. It would be advantageous to render the difficultly accessible naturally derived structure 1' and similar compounds available through total synthesis.
Scheme I' herein below depicts a typical enzymatic conversion of arachidonate with PGH synthase. ##STR4##